Effects of convulsants on handling-induced convulsions in mice selected for ethanol withdrawal severity

Abstract

Withdrawal seizure-prone (WSP) mice were genetically selected to express severe handling-induced convulsions (HIC) upon cessation of chronic ethanol vapor inhalation. The HIC is a sensitive measuer of CNS excitability, and the current paper compares the effects of elevenv convulsant drugs on the HIC in WSP and WSR (withdrawal seizure-resistant) mice, the latter selected for minimal alcohol withdrawal HIC. If WSP and WSR mice were differentially sensitive to a subset of the tested drugs, a common mechanism of action for that subset would imply that genes influencing that mechanism were important in determining ethanol withdrawal severity. All drugs significantly enhanced HIC in WSP mice. The magnitude of enhancement was small forN-methyl- d-aspartate (NMDA), kainic acid, BAY K 8644, Ro 15-4513, and strychnine; greater enhancement in WSP mice was seen after nicotine, and the direct and indirect γ-aminobutyric acid (GABA) antagonists bicuculline, 3-mercaptopropionic acid, picrotoxin,t-butylcyclophosphorothionate (TBPS), and pentylenetetrazol. Only two drugs, picrotoxin and pentylenetetrazol, had a marked effect on WSR mice: maximal effect of these drugs was equivalent in WSP and WSR mice. However, picrotoxin and pentylenetetrazol were more potent in WSP than in WSR mice. Three other GABA antagonists, bicuculin, 3-mercaptopriopionic acid, and TBPS, had a very small effect in WSR mice: these drugs also seemed to be more potent in WSP than in WSR mice. For all other tested drugs, maximal effect in WSP mice was much greater in WSP than in WSR mice. Given the minimal response of WSR mice to these other drugs, it was not possible to estimate potency, or to compare it with potency in WSP mice. WSP mice were clearly more sensitive to all tested drugs than WSR mice. Since WSP and WSR mice differed least in sensitivity to GABA-related compounds, these results suggest that differences in brain GABA systems may not be critical for the expression of genetic susceptibility or resistance to ethanol withdrawal severity. However, similar studies in animals withdrawing from ethanol may provide a better method for evaluating potential neuropharmacological correlates of withdrawal.